Diseases involving the peripheral nervous system are common in clinical medicine and yet many of the basic processes by which nerves are injured and repaired are not understood. We have studied the changes in ultrastructure and axoplasmic transport in the simplest model of axonal disease involving motor neurons, i.e., axotomy. More recently we have shown that tetanus toxin is carried to the CNS by retrograde intra-axonal transport. The purpose of this research grant is to obtain funds to continue our studies of the axotomy model, the mechanisms of regeneration of axons, and the role of axonal flow in tetanus. We will also explore the pathogenesis of axonal neuropathies (acrylamide, IDPN, methyl N-butyl ketone, INH, and vitamin E deficiency). In these experimental models, the toxic or deficiency state is known to cause human disease or faithfully reproduces the pathological changes documented in human patients. These models are all associated with pathologic changes in axons, and it seems highly likely that they are associated with primary or secondary changes in axoplasmic flow. We propose to define the ultrastructural changes in these models and to relate these changes to several parameters of axonal transport (rapid anterograde, slow anterograde, retrograde). In addition we propose to assess the ability of "intoxicated" neurons to mount a regenerative response. Using this approach, we believe we can define some of the pathogenetic mechanisms causing disorders of the huma nervous system.